The present invention relates to novel piperidine derivatives, their manufacture and use as medicaments.
The subject invention provides compounds of the formula: 
wherein
R1 is naphthyl or naphthyl substituted by one to three C1-C5-alkoxy groups;
R2 is phenyl; phenyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C1-C3-alkoxy, and nitro; benzyl; or benzyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C1-C3-alkoxy, and nitro;
R3 is hydroxymethyl, imidazolylmethyl, triazolylmethyl, Hxe2x80x94[CH(OR4)]2xe2x80x94 CH2xe2x80x94, Hxe2x80x94[CH(OR4)]2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, or R3axe2x80x94(CH2)kxe2x80x94[CH(OR4)]1xe2x80x94CH2xe2x80x94Oxe2x80x94;
R3a is hydrogen, hydroxy, imidazolyl, triazolyl, C1-C3-alkoxy, C1-C3-alkoxy-C2-C3-alkoxy, hydroxy-C2-C3-alkoxy, C1-C3-alkylamino or C1xe2x80x94C3-dialkylamino;
R4 is hydrogen or C1-C3-alkyl;
k is 1 or 2, when R3a is hydrogen, k is 0;
l is 1 or 2; or
and pharmaceutically acceptable salts thereof.
While the substituents are above listed collectively, all combinations of the mentioned substituents are enabled and described. For example, R1 can be naphthyl or naphthyl substituted by one to three C1-C5-alkoxy groups, preferably one C1-C3-alkoxy group, such as methoxy, and in particular 4-methoxy-naphthalen-2yl.
Similarly, R2 can be phenyl, or benzyl, or phenyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C1-C3-alkoxy, and nitro, or benzyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C1-C3-alkoxy, and nitro. Preferred R2s include phenyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C1-C3-alkoxy, and nitro, and benzyl substituted by one to three substituents independently selected from the group consisting of halogen, cyano, C1-C3-alkoxy, and nitro. More preferred R2 groups include phenyl substituted by one to three C1-C3-alkoxy groups or by one to three C1-C3-alkoxy groups in combination with one to three halogens. Favorably, R2 is phenyl substituted by one to three C1-C3-alkoxy groups or phenyl substituted by one to three C1-C3-alkoxy groups in combination with one to three halogens. More preferred is where the C1-C3-alkoxy group is methoxy and the halogen is fluorine. Favored situations include R2 being 2-methoxy benzyl, 3-fluoro-2-methoxy-benzyl, 4-fluoro-2-methoxy-benzyl, 5-fluoro-2-methoxy-benzyl, 3,5-difluoro-2-methoxy-benzyl, and 4,5-difluoro-2-methoxy-benzyl.
R2 can also be benzyl substituted by one to three C1-C3-alkoxy groups or by one to three C1-C3-alkoxy groups in combination with one to three halogens. Of these, it is preferred that benzyl be substituted by one to three C1-C3-alkoxy groups or one to three C1-C3-alkoxy groups in combination with one to three halogens, for example 2-methoxybenzyl and fluoro-2-methoxybenzyls, such as. It is especially preferred where C1-C3-alkoxy group is methoxy and the halogen is fluorine.
Preferred R3s include hydroxymethyl, imidazolylmethyl, triazolylmethyl, Hxe2x80x94[CH(OR4)]2xe2x80x94CH2xe2x80x94, and Hxe2x80x94[CH(OR4)]2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94. Any of these groups can be used. It is preferred, however, when R4 is hydrogen. Also preferred is when R3 is R3a xe2x80x94(CH2)kxe2x80x94[CH(OR4)]1xe2x80x94CH2xe2x80x94Oxe2x80x94. In such situations it is preferred that R3a is hydroxy or C1-C3-alkoxy, or imidazolyl or triazolyl, C1-C3-alkoxy-C2-C3-alkoxy, or R3a is hydroxy-C2-C3-alkoxy, or C1-C3-alkylamino or C1-C3-dialkylamino. A favored R3a is 2-methoxy-ethoxy. Another is methylamino.
The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in understanding the invention but are not to be construed as limiting.
The invention relates to novel piperidine derivatives of general formula I 
wherein
R1 is naphthyl optionally substituted by one to three C1-C5-alkoxy groups;
R2 is phenyl or benzyl, optionally substituted by substituents independently selected from one to three halogen, cyano, C1-C3-alkoxy and nitro groups;
R3 is hydroxymethyl, imidazolylmethyl, triazolylmethyl, Hxe2x80x94[CH(OR4)]2xe2x80x94CH2xe2x80x94, or Hxe2x80x94[CH(OR4)]2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, or R3axe2x80x94(CH2)kxe2x80x94[CH(OR4)]1xe2x80x94CH2xe2x80x94Oxe2x80x94;
R3a is hydrogen, hydroxy, imidazolyl, triazolyl, C1-C3-alkoxy, C1-C3-alkoxy-C2--C3-alkoxy, hydroxy-C2-C3-alkoxy, C1-C3-alkylamino or C1-C3-dialkylamino;
R4 is hydrogen or C1-C3-alkyl;
k is 1 or 2, when R3a is hydrogen, k is 0;
l is 1 or 2; and
pharmaceutically acceptable salts thereof.
The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or adjuvant.
The piperidine derivatives of the present invention have an inhibitory activity on the natural enzyme renin. Accordingly, they can be used for the treatment of disorders which are associated restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency. In addition, the present invention relates to a method for the prophylactic and/or therapeutic treatment of diseases which are associated with restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency, which method comprises administering a compound of formula (I) to a human being or an animal. Furthermore, the present invention relates to the use of such compounds for the preparation of medicaments for the treatment of disorders which are associated restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency.
The present invention also relates to processes for the preparation of the compounds of formula (I).
WO 97/09311 discloses piperidine derivatives of similar structure. However, these compounds display a high lipophilicity.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
In this specification the term xe2x80x9clowerxe2x80x9d is used to mean a group consisting of one to seven, preferably of one to four carbon atom(s).
The term xe2x80x9calkylxe2x80x9d refers to a branched or straight chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms, unless otherwise indicated. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the like.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, bromine and iodine, with chlorine and fluorine being preferred.
The term xe2x80x9calkoxy-xe2x80x9d refers to the group Rxe2x80x2xe2x80x94Oxe2x80x94, wherein Rxe2x80x2 is alkyl.
The term xe2x80x9calkylamino-xe2x80x9d refers to the group HRxe2x80x2Nxe2x80x94, wherein Rxe2x80x2 is alkyl, The term xe2x80x9cdi-alkylaminoxe2x80x9d refers to the group Rxe2x80x2Rxe2x80x3Nxe2x80x94, wherein Rxe2x80x2 and Rxe2x80x3 are alkyl.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d embraces salts of the compounds of formula (I) with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulphonic acid and the like, which are non-toxic to living organisms.
In detail, the present invention refers to compounds of formula (I) 
wherein
R1 is naphthyl optionally substituted by one to three C1-C5-alkoxy groups;
R2 is phenyl or benzyl, optionally substituted by substituents independently selected from one to three halogen, cyano, C1-C3-alkoxy and nitro groups;
R3 is hydroxymethyl, imidazolylmethyl, triazolylmethyl, Hxe2x80x94[CH(OR4)]2xe2x80x94CH2xe2x80x94, or Hxe2x80x94[CH(OR4)]2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, or R3axe2x80x94(CH2)kxe2x80x94[CH(OR4)]1xe2x80x94CH2xe2x80x94Oxe2x80x94;
R3a is hydrogen, hydroxy, imidazolyl, triazolyl, C1-C3-alkoxy, C1-C3-alkoxy-C2-C3-alkoxy, hydroxy-C2-C3-alkoxy, C1-C3-alkylamino or C1-C3-dialkylamino;
R4 is hydrogen or C1-C3-alkyl;
k is 1 or 2, when R3a is hydrogen, k is 0;
l is 1 or 2; and
pharmaceutically acceptable salts thereof.
The compounds of formula I have at least three asymmetric carbon atoms and can exist in the form of optically pure enantiomers, racemates, diastereomer mixtures, diastereomeric racemates, mixtures of diastereomeric racemates, in which the relative configuration of the three piperidine ring substitutents has to be all-trans as shown in formula I. The invention embraces all of these forms. Racemates, diastereomeric mixtures, diastereomeric racemates or mixtures of diastereomeric racemates can be separated according to usual methods, e.g. by column chromatography, thin-layer chromatography, HPLC and the like.
More particularly, the present invention relates to compounds of the above formula (I), wherein R1 is naphthyl optionally substituted by one C1-C3-alkoxy group. In a more preferred embodiment R1 is naphthyl substituted by one C1-C3-alkoxy group, preferably methoxy. In a further preferred embodiment, the alkoxy group is in meta position to the substituent providing the connection with the piperidine residue of the compounds of formula (I).
In a preferred embodiment, R2 is benzyl substituted by one to three C1-C3-alkoxy groups or by one to three C1-C3-alkoxy groups in combination with one to three halogens. Preferably the benzyl group is substituted by one C1-C3-alkoxy or by one C1-C3-alkoxy group in combination with one to two halogens. The preferred C1-C3-alkoxy group is methoxy, the preferred halogen is fluorine. In a more preferred embodiment, the above mentioned alkoxy group is in ortho position to the substituent providing the connection with the phenylpiperidine of the compounds of formula (I).
In a preferred embodiment, the present invention comprises the above compounds wherein R3a is hydroxy or C1-C3-alkoxy.
Particularly, the invention relates to compounds wherein R3 is R3axe2x80x94(CH2)kxe2x80x94[CH(OR4)]1xe2x80x94CH2xe2x80x94Oxe2x80x94 or Hxe2x80x94[CH(OR4)]2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94.
In a preferred embodiment, the invention comprises the above compounds wherein l is 1.
More particularly, the invention relates to compounds wherein R3 is CH3xe2x80x94Oxe2x80x94CH2xe2x80x94CH(OR4)xe2x80x94CH2xe2x80x94, Hxe2x80x94[CH(OH)]2xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, or HOxe2x80x94CH2xe2x80x94CH(OR4)xe2x80x94CH2xe2x80x94Oxe2x80x94.
Particularly, the invention relates to the above compounds wherein R4 is hydrogen.
The invention especially discloses compounds of formula (I) and pharmaceutically acceptable salts thereof, selected from
1) (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol;
2) (S)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol;
3) (R)-1-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-(2-methoxy-ethoxy)-propan-2-ol;
4) (R)-1-[(3S,4R,5R)-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methylamino-propan-2-ol;
5) 2-[3-[4-[(3S,4R,5R)-3-[(R)-2,3-dihydroxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile;
6) 2-[3-[4-[(3S,4R,5R)-3-[(R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile;
7) 2-[3-[4-[(3S,4R,5R)-3-[(R)-2-hydroxy-3-(2-methoxy-ethoxy)-propoxy]-5-4-methoxy-naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenoxy]-propoxy]-benzonitrile;
8) (R)-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-propane-1,2-diol;
9) (R)-1-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy]-3-[1,2,4]triazol-1-yl-propan-2-ol;
10) (R)-1-imidazol-1-yl-3-[(3S,4R,5R)-5-(4-methoxy-naphthalen-2-ylmethoxy)-4-[4-[3-(2-nitro-phenoxy)-propoxy]-phenyl]-piperidin-3-yloxy)-propan-2-ol;
11) (R)-3-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy]-piperidin-3-yloxy]-propane-1,2-diol;
12) (R)-3-[(3S,4R,5R)-4-[4-[3-(2-chloro-phenoxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propane-1,2-diol;
13) (R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
14) (3S,4R,5R)-[4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yl]-methanol;
15) (3S,4R,5R)-3-imidazol-1-ylmethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine dihydrochloride;
16) (S)-3-[(3S,4R,5R)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
17) (R)-3-[(3S,4R,5R)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
18) (S)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
19) (R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol;
20) (R)-1-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-ol;
21) (R)-1-[(3S,4R,5R)-4-[4-[3-(3-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-ol;
22) (R)-1-[(3S,4R,5R)-4-[4-[3-(4-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-ol;
23) (R)-1-[(3S,4R,5R)-4-[4-[3-(4,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-ol;
24) (R)-1-[(3S,4R,5R)-4-[4-[3-(3,5-difluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4- methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-ol; and
25) (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol.
An especially preferred compound is (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol and pharmaceutically acceptable salts thereof.
A further especially preferred compound is (R)-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propane-1,2-diol and pharmaceutically acceptable salts thereof.
A further especially preferred compound is (R)-3-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy]-piperidin-3-yloxy]-propane-1,2-diol and pharmaceutically acceptable salts thereof.
A further especially preferred compound is (R)-1-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-3-methoxy-propan-2-ol and pharmaceutically acceptable salts thereof.
A further especially preferred compound is (R)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-ylmethoxy]-propan-2-ol and pharmaceutically acceptable salts thereof.
The invention also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant. The pharmaceutical compositions may comprise in addition one or more compounds active against restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency. Examples for these additional compounds are angiotensin converting enzyme-inhibitors) e.g. captopril, lisinopril, enalapril and cilazapril; angiotensin-(1)-receptor antagonists, e.g. lorsartan and valsartan; diuretica, e.g. hydrochlorothiazide, mefrusid and furosemid; endothelin receptor antagonists, e.g. bosentan; endothelin converting enzyme inhibitors or neutral endopeptidase inhibitors; calcium channel blockers (antagonists), e.g. nifedipine, verapamil, and diltiazem; nitrates, e.g. glyceroltrinitrates (nitroglycerin) and isosorbid-dinitrates; beta-receptor blockers, e.g. carvedilol, alprenolol and propranolol; alpha-1 adrenoceptor antagonists, e.g. prazosin and terazosin; and reserpin.
A further embodiment of the present invention refers to the use of a compound as defined above for the preparation of medicaments for the treatment or prophylaxis of restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency.
An additional embodiment of the invention relates to a method for the prophylactic and/or therapeutic treatment of disorders in which renin plays a significant pathological role, especially restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency which method comprises administering a compound as defined above to a human being or an animal.
The compounds as defined above may be manufactured by cleaving off the protecting group P1 and optionally hydroxy protecting groups which may be present in compounds of formula (II) 
wherein P1 represents a NH-protecting group and the remaining symbols have the significance given above wherein hydroxy groups which may be contained in R1, R2, and R3 may optionally be present in protected form. If desired, reactive groups may be functionally modified in the thus-obtained compound of formula I (e.g. into esters) and/or converted into a pharmaceutically usable salt.
The cleavage of a protecting group P1 and hydroxy protecting groups which may be present can be carried out in a manner known per se. Examples of protecting groups P1 are usual amino protecting groups such as tert-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, alkylsilylalkyloxycarbonyl such as 2-(trimethylsilyl)ethoxycarbonyl, and trichloroethoxycarbonyl. Examples of hydroxy protecting groups are ether-protecting groups such as tetrahydropyranyl, allyl, 2-(trimethylsilyl)ethoxymethyl, trityl, tert-butyldimethylsilyl or ester protecting groups such as acetyl. Examples of diol protecting groups are cyclic ether protecting groups such as isopropylidene or benzylidene.
The cleavage of these protecting groups is effected by acidic or basic hydrolysis, by reductive methods or by means of Lewis acids or fluoride salts. A solution of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like in an inert solvent or solvent mixture is advantageously used for the acidic hydrolysis. Suitable solvents are alcohols such as methanol or ethanol, ethers such as tetrahydrofuran or dioxan, chlorinated hydrocarbons such as methylene chloride, and the like. Alkali metal hydroxides and alkali metal carbonates such as potassium hydroxide or sodium hydroxide or potassium carbonate or sodium carbonate, organic amines such as piperidine, and the like can be used for the basic hydrolysis. Inert organic solvents as referred to above for the acidic hydrolysis can be used as solubilizers. The reaction temperature for the acidic and basic hydrolysis can be varied in a range from 0xc2x0 C. to the reflux temperature, with the reaction preferably being carried out at between about 0xc2x0 C. and room temperature. The tert-butoxycarbonyl group is conveniently cleaved off with hydrochloric acid, hydrogen chloride, trifluoroacetic acid or formic acid in the presence or absence of an inert solvent. Furthermore, the tert-butoxycarbonyl group can be cleaved off by means of anhydrous zinc bromide in the presence of an inert solvent, preferably methylene chloride. The cleavage of the trichloroethoxycarbonyl group can be advantageously effected reductively with zinc in glacial acetic acid. The reaction temperature can lie in a range of 0xc2x0 C. to 40xc2x0 C., with the reaction preferably being carried out at room temperature. The cleavage of the 2-(trimethylsilyl)ethoxycarbonyl group can be effected by means of fluoride ions in the presence of an inert solvent such as acetonitrile, dimethyl sulphoxide, dimethylformamide or tetrahydrofuran, preferably by means of tetrabutylammonium fluoride in tetrahydrofuran, at temperatures from about 0xc2x0 C. to about room temperature.
The compounds of formula (II) are novel and are also an object of the invention. Their preparation is described in more detail hereinafter in Schemes 1-4 and in the Examples. 
Derivatives of general formula 2 in which P1* has, in addition to the meanings of P1, the meaning of benzyl or (R)- or (S)-2-phenethyl, can be obtained by alkylation of the 3-hydroxy function in a suitably N,4xe2x80x2xe2x80x94Oxe2x80x94di-protected 4-(4-hydroxy-phenyl)-1,2,3,6-tetrahydro-pyridin-3-ol of the general formula 1. The alkylation can be performed in solvents as ethers, like tetrahydrofuran and 1,2-dimethoxyethane, N,N-dimethylformamide or dimethylsulfoxide with aliphatic chlorides, bromides, iodides, tosylates or mesylates in the presence of a base like sodium hydride or potassium tert-butoxide. The alkylating agents used can contain optionally suitably protected functional groups which allow further structural modifications at a later stage of the synthesis. Hydroboration of the ether compounds formed (general formula 2) followed by subsequent basic oxidative working-up produces compounds of the general formula 3 with high diastereoselectivity, the isomer bearing only equatorial substituents at the piperidine ring being formed almost exclusively. The absolute stereochemistry at carbon 3 of the piperidine ring remains unaffected during the transformation of compounds 1 to compounds 3. The hydroboration can be effected according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, e.g. 1,2-dimethoxyethane, at a temperature between about 0xc2x0 C. and 70xc2x0 C., and with a diborane-containing or diborane-liberating reagent such as e.g. borane in tetrahydrofuran or a mixture of sodium borohydride and boron trifluoride etherate. The carboboranes which are formed as intermediates can be converted into the secondary alcohols of general formula 3 by reaction with bases, e.g. potassium hydroxide, and an oxidizing agent, e.g. hydrogen peroxide, at a temperature between about room temperature and 120xc2x0 C. Removal of the N- and O-protective functions and reintroduction of a optionally different N-protective group (P3), e.g. a N-Boc group, by well established procedures as e.g.: hydrogenolysis with hydrogen in the presence of a palladium catalyst followed by introduction of the Boc group with di-tert-butyldicarbonate in dioxan/water converts compounds of the general formula 3 into a compound of the general formula 4 bearing a phenolic and an aliphatic OH-function which can be derivatized selectively.
Selective derivatization of the phenolic function in compounds of general formula 4 can be performed by alkylation reactions using aliphatic chlorides, bromides, iodides, tosylates or mesylates in the presence of a base like potassium carbonate in solvents such as an ether like tetrahydrofuran, in N,N-dimethylformamide, dimethylsulfoxide, acetone, methyl-ethyl-ketone, or pyridine at temperatures between 0xc2x0 C. and 140xc2x0 C. leading to compounds of the general formula 5. The substituent introduced can function as a protecting group, being e.g. an allyl ether, or can be a unit which contains optionally suitably protected functional groups to allow further structural modifications at a later stage of the synthesis or consist of the whole substituent desired. Derivatization at the secondary hydroxy function of the piperidine ring can than be performed in solvents as ethers, like tetrahydrofuran or 1,2-dimethoxyethane, or in N,N-dimethylformamide or dimethylsulfoxide in the presence of an anion-forming base, like sodium hydride or potassium tert-butoxide, and a suitable alkylating agent, preferentially an aryl methyl chloride, bromide, mesylate or tosylate at temperatures between 0xc2x0 C. and 40xc2x0 C. thus giving compounds of the general formula 6. If R21 represents allyl, then this protective function can be replaced by a suitable substituent at any stage of the synthesis, e.g. by treatment with a palladium catalyst as palladium-II-acetate in the presence of triphenylphosphine and lithiumborohydride in a solvent like tetrahydrofuran or 1,2-dimethoxyethane followed by an alkylation procedure as described above. 
In case R31 contains a diol function protected as 1,3-dioxolane derivative, then the free diol can be liberated using hydrochloric acid in methanol, a procedure which also liberates the secondary amino function of the piperidine ring, if protected with a Boc-protective group. The Boc-protective function can optionally be reintroduced using di-tert-butyl-dicarbonate in a solvent, like a mixture of water and dioxane, methanol or acetonitril, in the presence of a base, like sodium hydrogencarbonate or triethylamine, leading to compounds of the general formula 7. A primary/secondary diol unit can be modified by transformation of e.g. the primary hydroxy function into a leaving group, e.g. a tosyloxy- or a mesyloxy-group. Selective tosylation of a primary hydroxy function in the presence of a secondary hydroxy function can be performed with tosyl chloride in a solvent like pyridine. If an excess of tosyl chloride is used, a short reaction time can prevent the formation of substantial amounts of the undesired ditosylate. Treatment of the monotosylate with base, e.g. with sodium hydroxide in dimethylsulfoxide, affords the corresponding oxiran 8. Optionally, the oxiran 8 can be prepared from the corresponding diol in a one step procedure by using reagents as diethoxytriphenylphosphorane (DTPP) in a solvent like dichloromethane or tetrahydrofuran, ether or 1,2-dimethoxyethane at temperatures between 40xc2x0 C. and 100xc2x0 C. under essentially neutral conditions (P. L. Robinson; J. W. Kelly; S. A. Evans, J. R. Phosphorus and Sulfur 1986, 26, 12-24). The oxiran opens regioselectively at the less hindered site when reacted with an alkali salt of an alcohol as methanol or methoxyethanol or an alkali salt of a heterocycle as [1,2,4]triazol or imidazol in a solvent like N,N-dimethylformamide, dimethylsulfoxide or an ether like tetrahydrofuran to give compounds of the general formula 9. Final removal of e.g. a Boc-protective group can be performed in the presence of acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroactic acid in a variety of solvents such as alcohols and alcohol/water mixtures, ethers and chlorinated hydrocarbons. The Boc-protective group can also be removed with anhydrous zinc bromide in inert solvents such as dichloromethane leading to compounds of the general formula 10. 
Derivatives of general formula 14 in which P1* has, in addition to the meanings of P1, the meaning of benzyl can be obtained in accordance with Scheme 3 from the compound of general formula 11 (with R being e.g. methyl or ethyl; commercially available compounds, e.g. Aldrich) by reduction to the diol analogously to the process described by E. Jaeger and J. H. Biel in J. Org. Chem. 30(3), 740-744 (1965), followed by the introduction of a suitable protecting group for the primary alcohol, e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl, preferably trityl. The oxidation of the secondary alcohol of general formula 13 can be carried out in manner known per se, e.g. by using oxalyl chloride and dimethyl sulphoxide as described by A. J. Mancuso and D. Swern in Synthesis 1981, 165, to yield the ketone of general formula 14.
Compounds of general formula 16 can be obtained by reacting compounds of general formula 14 in a manner known per se with metal-organic derivatives, preferably lithium or magnesium derivatives, prepared from compounds of general formula 15 wherein P2 represents lower-alkoxy, preferably methoxy, or benzyloxy. The reaction with such a metal-organic compound is effected according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, at a temperature between about xe2x88x9278xc2x0 C. and 75xc2x0 C.
The compounds of general formula 17 can be obtained therefrom in the presence of an acid or another water-cleaving reagent, optionally in the presence of a base, in an organic solvent. As acids there come into consideration e.g. hydrochloric acid, trifluoroacetic acid or p-toluenesulphonic acid, and as the water-cleaving reagent there can be used e.g. phosphorus oxytrichloride in pyridine. The reaction temperature lies between 0-120xc2x0 C.; as solvents there can be used e.g. toluene, dimethylformamide or alcohols.
Compounds of general formula 18 can be obtained from compounds of general formula 17 by hydroboration and subsequent basic oxidative working-up. The hydroboration can be effected according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, e.g. 1,2-dimethoxyethane, at a temperature between about 0xc2x0 C. and 70xc2x0 C., and with a diborane-containing or diborane-liberating reagent such as e.g. borane in tetrahydrofuran or a mixture of sodium borohydride and boron trifluoride etherate. The carboboranes which are formed as intermediates can be converted into the secondary alcohols of general formula 18 by reaction with bases, e.g. potassium hydroxide, and an oxidizing agent, e.g. hydrogen peroxide, at a temperature between about room temperature and 120xc2x0 C. Hydroboration of compounds of the general formula 17, followed by basic oxidative working-up produces compounds of the general formula 18 with high diastereoselectivity; the isomer bearing only equatorial substituents at the piperidine ring is almost exclusively formed.
Compounds of formula 18 in which P2 is lower-alkoxy can be converted into compounds of general formula 19 by an alkyl-aryl ether cleavage. The ether cleavage is effected according to methods known per se by, preferably starting from compounds in which P2 has the meaning methoxy, reacting the alkyl-aryl ether with mineral acids such as hydrobromic acid or hydriodic acid or preferably with Lewis acids such as boron trichloride or boron tribromide in a solvent which is inert under the reaction conditions, such as e.g. a halogenated hydrocarbon, at a temperature between about xe2x88x9210xc2x0 C. and room temperature. Under these conditions, the protecting group P4 which, preferably, has the meaning trityl, tert-butyl-diphenylsilyl or tert-butyl-dimethylsilyl, is also cleaved.
Compounds of formula 19 in which P2 is benzyl can be converted into compounds of general formula 20 by hydrogenolysis with hydrogen in the presence of a palladium catalyst in an inert solvent or solvent mixture. Suitable solvents are alcohols, such as methanol or ethanol, ethyl acetate and the like, at temperatures from about 0xc2x0 C. to 40xc2x0 C.
Compounds of formula 18 in which P2 is benzyl, P1 is benzyl and P4 is trityl can directly be converted into compounds of general formula 20 by hydrogenolysis with hydrogen in the presence of a palladium catalyst under conditions mentioned above. 
After removal of the N- and O-protecting functions compounds of formula 21 can be obtained by reintroduction of an optionally different N-protecting group, preferably tert-butoxycarbonyl, by well established procedures. The introduction of tert-butoxycarbonyl can be selectively effected by the reaction of compounds of general formula 20 with di-tert-butyldicarbonate in dioxan/water at temperatures from about xe2x88x9210xc2x0 C. to room temperature.
Compounds of general formula 21 can be used as starting materials for the preparation of compounds of general formula 22 in which R22 is the group xe2x80x94(CH2)3xe2x80x94Oxe2x80x94R2 with the meanings referred to above. The linkage of the group xe2x80x94(CH2)3xe2x80x94Oxe2x80x94R2 can be effected selectively by reaction with a derivative of the group to be introduced which carries a suitable leaving group. The selective linkage with the phenolic alcohol is effected according to alkylation methods which are known per se in the presence of a base such as potassium carbonate. Chlorides, bromides, iodides, tosylates or mesylates come into consideration as alkylating agents. The reaction is effected in a solvent which is inert under the reaction conditions, such as e.g. an ether such as tetrahydrofuran or an aromatic hydrocarbon such as e.g. toluene, pyridine, acetone or methyl ethyl ketone, at a temperature between about 0xc2x0 C. and 100xc2x0 C.
Compounds of general formula 23 can be obtained by introduction of a protecting group P4 selective for primary alcohols and selectively cleavable at an appropriate later stage of the reaction sequence in presence of the N-protecting group and the other functionalities. Examples of such hydroxy protecting groups are tert-butyldimethylsilyl, tert-butyldiphenylsilyl, and preferably trityl.
Compounds of general formula 24 can be obtained from 23 by alkylation with a compound which yields the group xe2x80x94CH2xe2x80x94R1. The alkylation of the secondary alcohol is effected according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, e.g. tetrahydrofuran or 1,2-dimethoxyethane, or dimethylformamide, with the aid of an alcoholate-forming base, e.g. sodium hydride, at a temperature between about 0xc2x0 C. and 40xc2x0 C. and using a halide, preferably chloride or bromide, or a sulfonic acid ester, e.g. a mesylate or tosylate, as the compound which yields the group xe2x80x94CH2xe2x80x94R1.
Compounds of general formula 25 can be obtained from 24 by selective cleavage of protecting group P4. The cleavage of these protecting groups is effected by acidic hydrolysis or by means of Lewis acids. The trityl group is conveniently cleaved off with a mixture of trifluoroacetic acid and trifluoroacetic acid anhydride in the presence of an inert solvent, preferably dichloromethane in a very short time at temperatures from about xe2x88x9210xc2x0 C. to 0xc2x0 C. The cleavage of the silyl protecting groups can be effected by means of fluoride ions in the presence of an inert solvent such as acetonitril, dimethylsulphoxide, N,N-dimethylformamide or tetrahydrofuran, preferably by means of tetrabutylammonium fluoride in tetrahydrofuran, at temperatures from about 0xc2x0 C. to about room temperature.
Compounds of general formula 26 can be obtained from 25 by alkylation with a compound which yields the group R33, where R33 has the meaning of Hxe2x80x94[CH(OR4)]2xe2x80x94CH2xe2x80x94. The alkylation of the primary alcohol is effected according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, e.g. tetrahydrofuran or 1,2-dimethoxyethane, or dimethylformamide, with the aid of an alcoholate-forming base, e.g. sodium hydride, at a temperature between about 0xc2x0 C. and 40xc2x0 C. and using a halide, preferably chloride or bromide, or a sulfonic acid ester, e.g. a mesylate or tosylate, as the compound which yields the group R33. Optionally, the alkylating agents used can contain suitably protected functional groups which allow further structural modifications at a later stage of the reaction sequence. As alkylating agent there comes into consideration e.g. allylbromide which then can be hydroxylated according to methods known per se, or (R)-(xe2x88x92)-2,2-dimethyl-4-(hydroxymethyl)-[1,3]dioxolane-p-toluenesulfonate. In case the diol function is protected as a 1,3-dioxolane derivative, then the free diol can be liberated using hydrochloric acid in methanol, a procedure which also liberates the secondary amino function of the piperidine ring, if protected by a Boc-group. The Boc-protective function can optionally be reintroduced using di-tert-butyl-dicarbonate in a solvent, like a mixture of water and dioxane, methanol or acetonitril, in the presence of a base, like sodium hydrogencarbonate or triethylamine. The resulting primary/secondary diol unit can be manipulated analogously as described for compounds of the general formula 8, 9 and 10.
Compounds of general formula 27 in which R34 is imidazolyl or triazolyl can be obtained from compounds of general formula 25. The reaction is effected according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, e.g. tetrahydrofuran or 1,2-dimethoxyethane, or N,N-dimethylformamide, with the aid of an anion-forming base, e.g. sodium hydride, at a temperature between about 0xc2x0 C. and 40xc2x0 C. and using a sulfonic acid ester, e.g. a tosylate, mesylate or triflate, as the activated derivative of the primary alcohol.
Compounds of general formula 27 where R34 has the meaning of Hxe2x80x94[(CH(OR4)]2xe2x80x94 can be obtained by transforming compounds of general formula 25 into the corresponding halides, preferably into chlorides or bromides, reacting them with metallorganic reagents according to methods known per se, e.g. with vinylmagnesium bromide in an inert solvent like tetrahydrofuran, and hydroxylating them according to methods known per se.
Piperidines of general formula 25, 26 and 27 can also be obtained in optically pure form. Separation into antipodes can be effected according to methods known per se, preferably at an early stage of the synthesis by salt formation with an optically active acid. For example, compounds of general formula 18 in which P1* has the meaning of benzyl can be obtained in their optically pure form by treatment with (+)- or (xe2x88x92)-mandelic acid and separation of the diastereomeric salts by fractional crystallization. Or, at a later stage, by derivatization with a chiral auxiliary substance such as, for example, (+)- or (xe2x88x92)-camphamoyl chloride and separation of the diastereomeric products by chromatography and/or crystallization and subsequent cleavage of the bond to the chiral auxiliary substance. In order to determine the absolute configuration of the piperidine derivative obtained, the pure diastereomeric salts and derivatives can be analyzed by conventional spectroscopic methods, with X-ray spectroscopy on single crystals being an especially suitable method.
Starting compounds 1 are known in the art and may be prepared according to the methods described in WO97/09311 or according to a reaction wherein a compound of formula 28 or a salt thereof 
wherein A is arylene; R1xe2x80x2 is xe2x80x94C*R3xe2x80x2R4xe2x80x2R5xe2x80x2; R2xe2x80x2 is xe2x80x94O-alkyl, xe2x80x94O-cycloalkyl, xe2x80x94O-alkenyl, or a group xe2x80x94OP2 as defined above, xe2x80x94O-aryl, xe2x80x94O-aralkyl, xe2x80x94O-aralkoxyalkyl, xe2x80x94O-alkylsulfonyl, xe2x80x94O-arylsulfonyl, chlorine, bromine or iodine; R3xe2x80x2 is hydrogen; R4xe2x80x2 is aryl; R5xe2x80x2 is alkyl, cycloalkyl, aryl, alkoxyalkyl or hydroxyalkyl; and, wherein C* is an asymmetric carbon atom; is epoxidated, optionally followed by isolation of the desired stereoisomer, resulting in a compound of formula 29 
The reaction may be performed by transforming a compound of general formula 28 into a halohydrine which by treatment with base gives the epoxide of general formula 29.
In detail, examples for compounds which are known for use in such epoxidation reactions are halogens and organic bromo-compounds such as N-bromosuccinimide, dibromoisocyanurate and 1,3-dibromo-5,5-dimethylhydantoin. Preferred is bromine, especially in the presence of an acid, preferably HBr and chemical equivalents thereof. Inert solvents taken alone or in combination can be used, particularly, solvents which are known for their utilization in epoxidation reactions. Examples of such solvents are straight or cyclic ethers dimethylether, diethylether, tetrahydrofuran and monoglyme or diglyme alone or in such a combination that a sufficient miscibility with water is given. A preferred solvent is dioxane. Preferred is the above reaction in the presence of an acid. Examples of such acids are optically active or inactive acids such as the hydrohalic acids, sulfonic acids and H2SO4. Particularly preferred is HBr. In general the above reaction can be performed in a wide pH range. Preferred is a pH range from about 1 to 4 and particularly preferred is a pH range from about 1,5 to 3. A temperature range of from about xe2x88x9220xc2x0 C. to the boiling point of the solvent is suitable for the reaction of the present invention. The preferred temperature range is between about xe2x88x9220xc2x0 C. to about 20xc2x0 C. preferably from about 0xc2x0 C. to about 5xc2x0 C.
The above reaction is followed by addition of a base such as NaOH, KOH, or a nitrogen-base such as triethylamine. Preferred is the use of NaOH or KOH. The temperature range for the addition of the base is between xe2x88x9220xc2x0 C. and the boiling point of the solvent. Preferred is a temperature range between xe2x88x9220xc2x0 C. and 20xc2x0 C. Particularly preferred is the addition of the base between 0xc2x0 C. and 5xc2x0 C. In case the epoxidising agent reacts with a compound of the formula 28 without addition of an acid, the epoxide can be obtained without using a base.
According to the above process compounds of formula 29 are formed as a mixture of stereoisomers and particularly as a mixture of diastereomers, or only one of the diastereomers is formed. In a preferred aspect one of the diastereomers is formed preferably. Optionally the desired stereoisomer especially diastereomer can be isolated by methods known in the art such as crystallisation, chromatography or distillation, preferably crystallisation or chromatography. These methods also include the formation of salts or derivatives of compounds of the formula 29 and in a following step the separation of these salts or derivatives by the above methods. These methods, especially methods for the separation of diastereoisomers are well known in the art and are for example described in Houben-Weyl, Methods of Organic Chemistry (pp. Vol. E21, p. 81, 91).
Allylic alcohols of general formula 1 can be obtained from compounds of general formula 29 by rearrangement of the epoxide by a base. A preferred method is the reaction with a metal alcoholate such as potassium t-butoxide, aluminium isopropoxide, titanium (IV) t-butoxide, with a lithium amide such as lithium diisopropylamide or with an organolithium compound such as phenyllithium, sec-butyllithium or methyllithium to give a compound of the general formula 1.
Moreover, a preferred aspect of the above process is the reaction of a compound of the formula 29 or a salt thereof, with phenyllithium. Particularly preferred is the above reaction, wherein the desired stereoisomer of a compound of the formula 29 reacts with phenyllithium. Solvents for this reaction taken alone or in combination are for example: ethers such as tetrahydrofuran, diethyl ether, or tert-butyl methyl ether, aromatic hydrocarbons such as toluene or chlorobenzene or pyridine. The solvent, which is preferred, depends on the reagent. In the case of phenyllithium as the reagent, tert-butyl methyl ether is a particularly preferred solvent.
The rearrangement of the epoxide can be performed in a temperature range from about xe2x88x9240xc2x0 C. up to the boiling of the solvent. Preferred is a temperature range from about xe2x88x9225xc2x0 C. up to 0xc2x0 C. Particularly preferred is a temperature of about xe2x88x9215xc2x0 C.
The present invention relates to all compounds of formula (I), whenever prepared by one of the processes described above.
The invention also relates to compounds as defined above for the treatment of diseases which are associated with restenosis, glaucoma, cardiac infarct, high blood pressure and end organ damage, e.g. cardiac insufficiency and kidney insufficiency.
The compounds of formula I and their pharmaceutically usable salts have an inhibitory activity on the natural enzyme renin. The latter passes from the kidneys into the blood and there brings about the cleavage of angiotensinogen with the formation of the decapeptide angiotensin I which is then cleaved in the lungs, the kidneys and other organs to the octapeptide angiotensin II. Angiotensin II increases blood pressure not only directly by arterial constriction, but also indirectly by the liberation of the sodium ion-retaining hormone aldosterone from the adrenal gland, with which is associated an increase in the extracellular fluid volume. This increase is attributed to the action of angiotensin II itself or to that of the hepapeptide angiotensin III which is formed therefrom as a cleavage product. Inhibitors of the enzymatic activity of renin bring about a decrease in the formation of angiotensin I and as a consequence of this the formation of a smaller amount of angiotensin II. The reduced concentration of this active peptide hormone is the direct reason for the blood pressure-lowering activity of renin inhibitors.
The in-vitro potency of renin inhibitors can, as described by W. Fischli et al. in Hypertension, Vol. 18 (1), 22-31 (1991) or Hypertension Vol. 22 (1), 9-17 (1993) be demonstrated experimentally by means of the tests described hereinafter. The tests can be carried out in analogy to those described by D. T. Pals et al. in Hypertension Vol. 8, 1105-1112 (1986) or J. Boger et al. in J. Med. Chem. 28, 1779-1790 (1985) or J. F. Dellaria et al. in J. Med. Chem. 30, 2137-2144 (1987) or T. Kokubu et al. in Biochem. Biophys. Res. Commun. 118, 929-933 (1984):
In Vitro Test with Pure Human Renin
The test is carried out in Eppendorf test tubes. The incubation mixture consists of (1) 100 xcexcl of human renin in buffer A (0.1 M sodium phosphate solution, pH 7.4, containing 0.1% bovine serum albumin, 0.1% sodium azide and 1 mM ethylenediaminetetraacetic acid), sufficient for a renin activity of 2-3 ng of angiotensin I/ml/hr.; (2) 145 xcexcl of buffer A: (3) 30 xcexcl of 10 mM human tetradecapeptide renin substrate (hTD) in 10 mM hydrochloric acid: (4) 15 xcexcl of dimethyl sulphoxide with or without inhibitor and (5) 10 xcexcl of a 0.03 molar solution of hydroxyquinoline sulphate in water.
The samples are incubated for three hours at 37xc2x0 C. and, respectively, 4xc2x0 C. in triplicate. 2xc3x97100 xcexcl samples per test tube are used in order to measure the production of angiotensin I via RIA (standard radioimmunoassay; clinical assay solid phase kit). Cross reactivities of the antibody used in the RIA are: angiotensin I 100%; angiotensin II 0.0013%; hTD (angiotensin I-Val-Ile-His-Ser-OH) 0.09%. The production of angiotensin I is determined by the difference between the test at 37xc2x0 C. and that at 4xc2x0 C.
The Following Controls are Carried Out
(a) Incubation of hTD samples without renin and without inhibitor at 37xc2x0 C. and 4xc2x0 C. The difference between these two values gives the base value of the angiotensin I production.
(b) Incubation of hTD samples with renin, but without inhibitor at 37xc2x0 C. and 4xc2x0 C. The difference between these values gives the maximum value of the angiotensin I production.
In each sample the base value of the angiotensin I production is subtracted from the angiotensin I production which is determined. The difference between the maximum value and the base value gives the value of the maximum substrate hydrolysis (=100%) by renin.
The results are given as IC50 values which denote the concentration of the inhibitor at which the enzymatic activity is inhibited by 50%. The IC50 values are determined from a linear regression curve from a logit-log plot.
The results obtained in this test are compiled in the following Table:
It will be appreciated that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide prodrug derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such prodrugs include the physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters. Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
As mentioned earlier, medicaments containing a compound of formula (I) are also an object of the present invention, as is a process for the manufacture of such medicaments, which process comprises bringing one or more compounds of formula (I) and, if desired, one or more other therapeutically valuable substances into a galenical administration form.
The pharmaceutical compositions may be administered orally, for example in the form of tablets, coated tablets, dragxc3xa9es, hard or soft gelatine capsules, solutions, emulsions or suspensions. Administration can also be carried out rectally, for example using suppositories; locally or percutaneously, for example using ointments, creams, gels or solutions; or parenterally, e.g. intravenously, intramuscularly, subcutaneously, intrathecally or transdermally, using for example injectable solutions. Furthermore, administration can be carried out sublingually or as opthalmological preparations or as an aerosol, for example in the form of a spray.
For the preparation of tablets, coated tablets, dragxc3xa9es or hard gelatine capsules the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients for tablets, dragxc3xa9es or hard gelatine capsules include lactose, maize starch or derivatives thereof, talc or stearic acid or salts thereof.
Suitable excipients for use with soft gelatine capsules include for example vegetable oils, waxes, fats, semi-solid or liquid polyols etc.; according to the nature of the active ingredients it may however be the case that no excipient is needed at all for soft gelatine capsules.
For the preparation of solutions and syrups, excipients which may be used include for example water, polyols, saccharose, invert sugar and glucose.
For injectable solutions, excipients which may be used include for example water, alcohols, polyols, glycerine, and vegetable oils.
For suppositories, and local or percutaneous application, excipients which may be used include for example natural or hardened oils, waxes, fats and semi-solid or liquid polyols.
The pharmaceutical compositions may also contain preserving agents, solubilising agents, stabilising agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, salts for the variation of osmotic pressure, buffers, coating agents or antioxidants. As mentioned earlier, they may also contain other therapeutically valuable agents.
It is a prerequisite that all adjuvants used in the manufacture of the preparations are non-toxic.
Intravenous, intramuscular or oral administration is a preferred form of use. The dosages in which the compounds of formula (I) are administered in effective amounts depend on the nature of the specific active ingredient, the age and the requirements of the patient and the mode of application. In general, daily dosages of about 1 mgxe2x88x921000 mg, preferably 10 mg-300 mg, per day come into consideration.